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Raghavendra Rao et al. World Journal of Pharmaceutical Research
FORMULATION AND EVALUATION OF ORAL DISINTEGRATING
TABLETS OF MONTELUKAST SODIUM: EFFECT OF
FUNCTIONALITY OF SUPERDISINTEGRANTS
B. Shravani, N. G. Raghavendra Rao*, Gandra Pragna, M. Srikanth Reddy
Department of Pharmaceutics, Jyothishmathi Institute of Pharmaceutical science,
Thimmapur, Karimnagar- 505481, AP. India.
ABSTRACT
Montelukast Sodium is a leukotriene receptor antagonist (LTRA) used
for the treatment of asthma and to relieve symptoms of seasonal
allergies. Montelukast blocks the action of leukotriene on the cysteinyl
leukotriene receptor in the lungs and bronchial tubes by binding to it.
In present research work an attempt has been made to prepare fast
dissolving tablets of Montelukast sodium were prepared by using
direct compression method using superdisintegrants. IR spectral
analysis study showed that there was no drug interaction with
formulation additives of the tablet. The blend was examined for the
pre-compressional parameters results were within prescribed limits and
indicated good free flowing property. The prepared tablets
formulations were evaluated for post-compressional parameters. All
the post-compressional parameter are evaluated were prescribed limits and results were
within IP acceptable limits. The in-vitro disintegration time of Montelukast sodium fast
dissolving tablets were found to be in the range of 11 to 61 sec fulfilling the official
requirements. The in-vitro disintegration time of Montelukast sodium prepared by direct
compression method DC7 formulation containing CP 6 % shows around 11.52 sec. The
tablets prepared by direct compression method the t50% and t90%(time for 50% and 90% of
release) values decreased with increase in the level of CP. In all the prepared formulation 50
% and 90 % of drug release ranges between within ranges 0.95 min to 2.91 min and 3.60 min
to 8.92 min respectively. Among all formulations DC7 showed 99.85% drug release within 4
min. The stability study conducted as per the ICH guidelines and the formulations were found
to be stable. It was concluded that the rapidly disintegrating tablets with proper hardness,
World Journal of Pharmaceutical research
Volume 2, Issue 6, 2301-2316. Research Article ISSN 2277 – 7105
Article Received on 29 August 2013, Revised on 26 Sept. 2013,
Accepted on 20 October 2013
*Correspondence for Author: Dr N. G. Raghavendra Rao
Department of Pharmaceutics,
Jyothishmathi Institute of
Pharmaceutical science,
Thimmapur, Karimnagar-
505481, AP. India
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rapid disintegration in the oral cavity with enhanced dissolution rate can be made using super
disintegrants.
Keywords: Fast dissolving tablets, Montelukast sodium, sodium starch glycolate,
Crosscarmellose sodium, Crospovidone, Kyron-T-315.
INTRODUCTION
Oral delivery is currently the gold standard in the pharmaceutical industry where it is
regarded as the safest, most convenient and an economical method of drug delivery having
the highest patient compliance.1 Tablet is most popular among all dosage forms existing
today because of convenience of self administration, compactness and easymanufacturing.2
Many patients express difficulty in swallowing tablets and hard gelatin capsules, resulting in
noncompliance and ineffective therapy.3
To overcome this weakness, scientists have developed innovative drug delivery systems
known as fast dissolving tablets.4 United States Food and drug administration (FDA) defined
fast dissolving tablet (FDT) as “a solid dosage form containing medicinal substance or active
ingredient which disintegrate rapidly usually within a matter of seconds when placed up on
the tongue”.5 Their characteristic advantages such as administration without water, patient
compliance, rapid onset of action, increased bioavailability and good stability make these
tablets popular as a dosage form of choice in the current market.6
Montelukast sodium is chemically designated as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)
ethenyl] phenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropane
acetic acid, monosodium salt, an orally administered drug of choice in the treatment of
asthma in adults and children. Other problems like hand tremors, dysphagia in case of
geriatric and non co-operative patients and the problem of swallowing is common
phenomenon which leads to poor patient compliance. To overcome these drawbacks mouth
dissolving tablets or orally disintegrating tablets or fast dissolving tablets has emerged as an
alternative oral dosage form.7
The pediatric and geriatrics patients are of particular concern. To overcome this, dispersible
tablets 8 and fast-disintegrating tablets 9 have been developed. Most commonly used methods
to prepare these tablets are; freeze-drying/Lyophilization 10 tablet molding 11 and direct-
compression methods 12. Lyophilized tablets show a very porous structure, which causes
quick penetration of saliva into the pores when placed in oral cavity 10, 13. The main
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disadvantages of tablets produced are, in addition to the cost intensive production process, a
lack of physical resistance in standard blister packs and their limited ability to incorporate
higher concentrations of active drug 8. Moulded tablets dissolve completely and rapidly.
However, lack of strength and taste masking are of great concern14 . Main advantages of
direct compression are low manufacturing cost and high mechanical integrity of the tablets 15.
Therefore, direct-compression appears to be a better option for manufacturing of tablets.
In the present study an attempt had been made to prepare mouth dissolving tablets of
montelukast sodium in the oral cavity with enhanced dissolution rate and hence improved
patient compliance. The basic approach used in the development of mouth dissolving tablets
is the use of different superdisintegrants like croscarmellose sodium (CCS), sodium starch
glycolate (SSG), Kyron T134 and crospovidone (CP), which provide instantaneous
disintegration of tablet after putting on tongue, thereby releasing the drug in saliva. These
systems may offer superior profile with potential mucosal absorption, thus increase the drug
bioavailability. These systems are also called mouth dissolving tablets, melt-in-mouth tablets,
Reprimelts, porous tablets, oro dispersible, quick dissolving or rapidly disintegrating tablets.
MATERIAL AND METHODS
Montelukast sodium was procured as a gift sample from Redefining Healthcare, Unimark
Remedies Limited, Vapi, Gujarat, India. Superdisintegrants like crospovidone, sodium starch
glycolate, croscarmellose, kyron-T. Other excipients like Mannitol, Microcrystalline
cellulose, flavor, Sodium lauryl sulphate (SLS), Talc, and Magnesium stearate purchased
from S.D. Fine chem., Mumbai. All other materials were of analytical reagent grade.
Preparation of fast dissolving tablets by direct compression method 16, 17
Montelukast sodium fast dissolving tablets were prepared by direct compression method by
using co-processed superdisintegrants like CP, SSG, CCS, Kyron-T. Mannitol,
Microcrystalline Cellulose (MCC) as a diluents, Aspartame as a sweetening agent, Mint as a
flavor, Magnesium Stearate, Talc used as a lubricant and glidant. All the ingredients (except
granular directly compressible excipients) were passed through # 60-mesh separately. Then
the ingredients were weighed and mixed in geometrical order after sufficient mixing of drug
as well as other components and compressed into tablets of 200mg using 6 mm BB Tooling
round flat punches on 12- station rotary tablet machine. Compression force of the machine
was adjusted to obtain the hardness of 3-4 kg/cm2.
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Compatibility studies
IR Studies: IR spectra for pure drug Montelukast sodium and DC3, DC7, DC11 and DC15
powdered tablets were recorded in Infrared spectrophotometer with KBr pellets.
Evaluation of fast dissolving tablets of Montelukast sodium
Pre-compression Parameters: The tablet blends were evaluated for their bulk density,
tapped density, Carr’s index and flow properties.
Post-compression Parameters
Hardness test: The hardness of the tablets was determined using Pfizer hardness tester. It is
expressed in kg/cm2. Six tablets were randomly picked from each formulation and the mean
and standard deviation values were calculated.
Friability: A friability test was conducted on the tablets using Friabilator. A friability test
was conducted on the tablets using Friabilator. Twenty tablets were selected from each batch
and any loose dust was removed with the help of a soft brush. The tablets were initially
weighed (Winitial) and transferred into Friabilator. The drum was rotated at 25 rpm for 4 min
after which the mini-tablets were removed. Any loose dust was removed from the tablets as
before and the tablets were weighed again (Wfinal). The percentage friability was then
calculated by,
F = [(Winitial- Wfinal)/ Winitial] X 100
% Friability of tablets less than 1% is considered acceptable.
Weight variation: The weight variation test was conducted by weighing 20 randomly
selected tablets individually, calculating the average weight and comparing the individual
tablet weights to the average. The specification of weight variation is 10%.
Estimation of drug content 18: Five tablets weighted and crushed in a mortar then weighed
powder contain equivalent to 10 mg of drug transferred in 100ml of 0.5% of SLS solution to
give a concentration of 100µg/ml. Take 15ml of this solution and diluted it upto 100ml with
0.5% of SLS solution to give a concentration of 15µg/ml. Absorbance measured at 342nm
using UV-Visible Spectrophotometer.
Disintegration time 19: Tablet disintegration is an important step in drug absorption. The test
for disintegration was carried out in Electro lab USP disintegration test apparatus. It consists
of 6 glass tubes which are 3 inches long, open at the top, and held against a 10 mesh screen,
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at the bottom end of the basket rack assembly. To test the disintegration time of tablets, one
tablet was placed in each tube and the basket rack was positioned in a 1 liter beaker
containing 0.5% of SLS in water at 37°C ± 1°C such that the tablet remains 2.5 cm below the
surface of the liquid. The time taken for the complete disintegration of the tablets was noted.
Wetting time: 10 ml of distilled water containing Eosin, a water-soluble dye was placed in a
petri dish of 10 cm diameter. Tablets were carefully placed in the centre of the petri dish and
the time required for water to reach the upper surface of the tablet was noted as the wetting
time. The test results are presented as mean value of three determinations.
Water absorption ratio 20: A piece of tissue paper folded twice was placed in a small Petri
dish containing 6 ml of water. A tablet was put on the paper and the time required for
complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio
indicated by R, which is calculated by using the below mentioned equation.
In-vitro release 21-23 : The in-vitro release pattern of FDT was studied as per method given by
Chaudhari et al. In-vitro dissolution studies of FDT were performed at 37 ± 0.5°C using 0.5%
w/v aqueous solution sodium lauryl sulfate in USP II paddle method at 50 rpm. 5 mL of
filtered aliquot was manually withdrawn at pre-determined time intervals and replaced with
5 mL of fresh 0.5% sodium lauryl sulfate solution maintained at the same temperature. The
samples were analyzed at 342nm using a UV spectrophotometer.
Details of dissolution test:
Dissolution test apparatus : USP type II
Speed : 50 rpm
Stirrer : Paddle type
Volume of medium : 900 ml
Volume withdrawn : 5 ml
Medium used : 0.5% SLS in distilled water
Water Temperature : 37 ± 0.5ºC
The stability study24 of the tablets was carried out according to International conference on
Harmonization guidelines for zone III and IV. The formulations were stored at 25°C/ 60%
and 40C / 75 % RH for three months by storing the samples in stability chamber (Thermo
Lab, Mumbai).
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RESULT AND DISCUSSION
In the present study the IR spectra for pure drug Montelukast sodium and its formulations
like DC3, DC7, DC11 and DC15 with various polymers and other excipients is taken to
establish the physical characterization of drug and its formulations (Fig 1). The drug-
excipients study was done by Fourier transform infrared (FT-IR) spectroscopy study, the
prominent peaks of Montelukast sodium pure drug were shown at absorption peaks for the
drug montelukast sodium has got tertiary -OH groups exhibited a broad peak around 3300
cm-1 and a -COOH peak which is in the form of a salt has exhibited a strong peak near 1700
cm-1. The aromatic C-H peaks are also observed between 2900-3000 cm-1. In formulations
like DC3, DC7, DC11 and DC15 exhibited characteristic absorption peaks in the same range
of pure drug peak. Hence, it could be confirmed that there is no chemical interaction between
drug and excipients in the formulation.
The values of pre-compression parameters evaluated were within prescribed limits and
indicated good free flowing property (Table 2). All the post-compression parameters are
evaluated were prescribed limits and results were within IP acceptable limits. Results of post-
compression parameters were shown in (Table 3).
In all the formulations, hardness test indicated good mechanical strength ranges from 2.74
kg/cm2 to 3.52 kg/cm2. The friability range is 0.54 to 0.74 % to be well within the approved
range (<1%)indicated that tablet had good mechanical resistance. The weight variation was
found in all designed formulations in the range 196.81 to 200.44 mg. All the tablets passed
weight variation test as the average percentage weight variation was within 7.5% i.e. in the
pharmacopoeia limits. The standard deviation values indicated that all the formulations were
within the range.
The drug content uniformity was in between 97.26 to 99.91 %, water absorption ration were
found between 46.32 to 86.03% and wetting time between 68.31 to 97.48 sec. The results of
drug content, water absorption ration and wetting time were tabulated in Table 3. Rapid
disintegration within several minutes was observed in all the formulations. The in-vitro
disintegration data is tabulated in the (Table 3) and Fig 2-3. The in-vitro disintegration time
of fast dissolving tablets were found to be 11.52 to 61.44 sec. which is in the range of
fulfilling the official requirements. By the addition of superdisintegrants the disintegration
time increased significantly (P<0.05) tablets prepared.
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Table 1: Composition of mouth dissolving tablets of Montelukast Sodium
Ingredients
(mg) DC1 DC2 DC3 DC4 DC5 DC6 DC7 DC8 DC9 DC10 DC11 DC12 DC13 DC14 DC15 DC16
MS 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10
SSG 4 8 12 16 - - - - - - - - - - - -
CP - - - - 4 8 12 16 - - - - - - - -
CCS - - - - - - - - 4 8 12 16 - - - -
Kyron-T - - - - - - - - - - - - 4 8 12 16
Talc 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
Mg Stea 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
MCC 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40
Aspartame 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3
Flavor 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Mannitol 138 134 130 126 138 134 130 126 138 134 130 126 138 134 130 126
Total wt(mg) 200 200 200 200 200 200 200 200 200 200 200 200 200 200 200 200
* MS=Montelukast sodium, SSG= Sodium starch Glycolate, CP= Crospovidone, CCS= Crosscarmellose sodium, MCC=
Microcrystalline cellulose, Mg Stea= Magnesium stearate.
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Table 2: Post-compression parameters Montelukast Sodium fast dissolving tablets
FC
Bulk
density(g/cc)
SD, n=3
Tapped
density (g/cc)
SD, n=3
Angle of repose
(degree)
SD, n=3
Carr’s
index (%)
SD, n=3
Hausner’s
Ratio
SD, n=3
DC1 0.53 0.03 0.63 0.01 28.19 1.20 16.46 0.25 1.22 0.08
DC2 0.52 0.04 0.62 0.02 29.76 0.90 16.24 0.12 1.23 0.10
DC3 0.55 0.08 0.64 0.04 28.44 1.10 20.62 0.32 1.13 0.12
DC4 0.54 0.02 0.54 0.03 28.84 0.80 15.08 0.14 1.15 0.06
DC5 0.51 0.03 0.56 0.02 29.51 0.40 19.73 0.16 1.24 0.06
DC6 0.47 0.06 0.59 0.03 28.16 1.30 16.44 0.18 1.23 0.04
DC7 0.54 0.04 0.63 0.02 29.66 1.40 18.62 0.14 1.16 0.08
DC8 0.45 0.05 0.59 0.03 27.48 0.08 21.48 0.12 1.22 0.02
DC9 0.52 0.06 0.58 0.04 26.74 0.12 20.74 0.14 1.26 0.09
DC10 0.53 0.09 0.65 0.02 27.24 1.20 16.65 0.12 1.19 0.08
DC11 0.54 0.07 0.63 0.05 27.45 0.80 15.44 0.16 1.22 0.14
DC12 0.56 0.09 0.58 0.02 28.46 1.20 22.32 0.20 1.19 0.12
DC13 0.57 0.03 0.62 0.03 28.62 0.72 15.08 0.12 1.17 0.14
DC14 0.51 0.02 0.58 0.06 27.51 0.42 16.44 0.18 1.28 0.06
DC15 0.47 0.05 0.59 0.03 26.19 1.24 18.84 0.12 1.24 0.02
DC16 0.48 0.06 0.61 0.02 28.12 1.36 16.65 0.14 1.16 0.08
* Average of three determinations
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Table 3: Post-compression parameters of Montelukast Sodium fast dissolving tablets prepared by direct compression method
FC
Hardness * (Kg/cm²) SD, n=3
Friability (%) SD, n=3
Weight variation*
(mg) SD, n=20
Disintegration time* (sec) SD, n=3
Wetting time* (sec) SD, n=3
Water absorption ratio* SD, n=3
Drug Content* (%) SD, n=3
DC1 3.22 0.20 0.59 0.10 199.46 1.2 50.32 1.2 92.12 1.1 52.65 1.1 98.46 1.4 DC2 3.34 0.06 0.66 0.10 198.26 1.4 31.16 1.4 91.42 0.8 58.46 1.6 97.26 1.2
DC3 3.46 0.12 0.68 0.09 20 0.12 1.0 16.44 1.6 71.22 0.2 84.41 1.2 99.48 0.6
DC4 3.32 0.14 0.69 0.09 198.68 0.08 22.86 1.2 68.31 1.2 86.03 0.8 97.76 1.2
DC5 3.44 0.16 0.74 0.06 200.32 1.4 34.26 1.2 94.42 1.4 72.72 1.8 98.24 0.8 DC6 3.32 0.14 0.68 1.2 197.42 0.06 21.23 0.6 86.69 1.2 68.62 1.4 96.98 0.6 DC7 3.24 0.08 0.58 0.10 199.69 1.4 11.52 1.4 71.26 1.6 56.48 1.2 97.68 1.2 DC8 2.98 0.12 0.54 0.04 200.44 0.6 18.56 1.2 50.32 1.0 46.32 1.6 99.25 1.4 DC9 3.32 0.14 0.58 0.04 200.22 1.4 46.42 1.1 92.32 1.1 86.62 1.2 99.28 1.3 DC10 3.44 0.24 0.56 0.10 200.14 1.2 28.32 1.4 91.26 1.2 79.45 1.6 98.98 1.4 DC11 3.12 0.06 0.68 0.10 198.79 1.4 14.86 1.2 84.32 0.7 54.24 0.4 98.64 1.2 DC12 3.52 0.16 0.66 0.09 197.31 1.4 20.16 1.5 50.04 0.4 49.20 0.6 98.22 0.6 DC13 2.74 0.18 0.70 0.09 196.81 0.07 61.44 1.4 96.31 1.4 54.24 0.6 99.76 1.2 DC14 3.24 0.14 0.72 0.06 199.75 1.3 44.41 1.4 92.23 1.3 61.12 1.2 98.44 0.4 DC15 3.46 0.22 0.68 1.24 199.88 1.2 28.32 1.4 50.02 1.2 67.52 2.2 99.91 0.6 DC16 3.36 0.12 0.62 0.12 199.53 1.4 39.23 0.8 97.48 1.0 76.43 1.9 99.72 1.4
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Fig 1: IR Spectra of Pure drug Montelukast sodium, Formulation DC3, DC7, DC11
and DC15.
Fig 2: Disintegration time vs Formulation (DC1-DC8)
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Fig 3: Disintegration time vs Formulation (DC9 - DC16)
Table 4:Release profile of Montelukast sodium fast dissolving tablets prepared by direct
compression
Formulation Code T50 (min) T90 (min)
DC1 2.57 0.20 7.680.2 DC2 1.88 0.16 5.830.8 DC3 1.60 0.12 3.890.2 DC4 1.70 0.14 4.80 0.4 DC5 1.82 0.16 5.780.4 DC6 1.59 0.14 4.800.6 DC7 0.95 0.08 3.600.6 DC8 1.53 0.12 3.89 1.0 DC9 2.94 0.14 7.83 1.2
DC10 2.53 0.24 6.42 1.2
DC11 0.88 0.06 2.890.7
DC12 0.98 0.16 3.750.4
DC13 2.90 0.12 8.921.2
DC14 2.61 0.14 7.83 1.3
DC15 0.97 0.22 4.76 1.2
DC16 1.59 0.12 5.830.4
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Fig 4: Release profile of formulation containing SSG (DC1-DC4)
Fig 5: Release profile of formulation containing CP (DC5-DC8)
Fig 6: Release profile of formulation containing CCS (DC9-DC12)
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Fig 7: Release profile of formulation containing Kyron T (DC13-DC16)
Table 5: Result for stability study at different temperatures for 3 months
Sl.
No.
Formulation
code Month
Hardness
Kg/cm²
Percentage
Friability
Dispersion
time (sec)
25°C/60% RH
1 DC3
1st 3.46 0.68 16.44
2nd 3.49 0.68 17.12
3rd 3.52 0.67 17.82
2 DC7
1st 3.24 0.58 11.52
2nd 3.28 0.59 12.12
3rd 3.32 0.61 12.48
3 DC11
1st 3.12 0.68 14.86
2nd 3.14 0.68 15.14
3rd 3.13 0.69 15.36
40°C/75% RH
4 DC3
1st 3.46 0.68 16.44
2nd 3.48 0.69 16.58
3rd 3.52 0.67 17.12
5 DC7
1st 3.24 0.58 11.52
2nd 3.26 0.60 11.84
3rd 3.28 0.59 12.08
6 DC11 1st 3.12 0.68 14.86
2nd 3.18 0.67 15.14
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3rd 3.24 0.66 15.36
Based on the in-vitro disintegration time, formulation DC7 (8 % CP) were found to be
promising and showed a disintegration time of 11.52 sec (shown in Fig 2). These results
suggest that the disintegration times can be decreased by using wicking type
superdisintegrants (CP). Wetting time is closely related to the inner structure of the tablet.
In-vitro dissolution studies (Shown in Fig 4-7) of all the formulations were carried out in pH
1.2 buffer as dissolution medium. The release study results t50% and t90% are shown in
Table 4. The t50% and t90% values decreased with increase in the concentration of SSG, CCS
and CP. Among all the formulation BD9 (9 % CP) were found to be promising and showed a
disintegration time of 12 sec, 50 % of drug released in 1.02 min, and 90 % of drug released in
5.72 min.
The promising formulations were subjected to short term stability study by storing the
formulations at 25C/65% and 40oC/75% RH up to three month. The optimized formulations
DC3, DC7 and DC11 were selected. After three month the tablets were again analyzed for the
hardness, friability, drug content uniformity and disintegration time. The increase in the
disintegration time was observed in case of tablets prepared with direct compression method
No change was observed in the hardness, friability and disintegration time of tablets prepared
by direct compression, co-processed and solid dispersion method technique. No significant
change was observed in the of all formulation. The results were shown in Table 5.
CONCLUSION
In the present research work fast dissolving tablets of Montelukast Sodium were prepared by
direct compression method. All the tablets of Montelukast Sodium were subjected to weight
variation, hardness, friability, in-vitro disintegration time, drug polymer interaction, drug
content uniformity, water absorption ratio, wetting time, and in- vitro drug release. The
tablets prepared by direct compression method the t50% and t90% (time for 50% and 90% of
release) values decreased with increase in the level of CP. In all the prepared formulation by
direct compression method 50 % and 90 % of drug release ranges between within ranges
0.95 min to 2.91 min and 3.60 min to 8.92 min respectively. Among all formulations DC7
showed 99.85% drug release within 4 min. The stability study conducted as per the ICH
guidelines and the formulations were found to be stable. It was concluded that the rapidly
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disintegrating tablets with proper hardness, rapid disintegration in the oral cavity with
enhanced dissolution rate can be made using super disintegrants.
ACKNOWLEDGEMENTS
The authors are thankful Redefining Healthcare, Unimark Remedies Limited, Vapi, Gujarat,
India for providing Montelukast Soduim as a Gift sample. The authors are also thankful to
Sri. Juvadi Sagar Rao Garu, Chairman and Sri. K. Venkat Rao Garu, Director, Jyothishmathi
Institute of Pharmaceutical Science, Karimnagar, provide the facilities to carrying out this
research work.
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